Epigenetic regulation of transcription through covalent modifications of histones is a fundamental mechanism of transcriptional regulation that is important for stem cell self-renewal as well as lineage commitment during development. Two broad groups of transcriptional regulators, the Trithorax (Trx) and Polycomb group Pc(G) proteins are the pivotal positive and negative regulators in this mechanism. Deregulation of transcription by disruption of both of these families of epigenetic regulators is emerging as a common cause of human malignancies.
Mixed lineage leukemia protein, MLL, is a Trx group protein that can be disrupted by fusion to a variety of translocation partners in human lymphoid and myeloid acute leukemia. As a result of chromosome translocation, the MLL N-terminus becomes fused to one of more than 60 partner proteins forming chimeric oncogenes which up-regulate the expression of HOX genes, blocking the hematopoietic differentiation and ultimately lead to acute leukemia (see, e.g., Ayton P M, Cleary M L (2001) Oncogene 20: 5695-5707; Daser A, Rabbitts T H (2004) Genes & development 18: 965-974; Eguchi M, Eguchi-Ishimae M, Greaves M (2003) International journal of hematology 78: 390-401; Krivtsov A V, Armstrong S A (2007) Nature reviews Cancer 7: 823-833). Leukemia mediated by MLL rearrangements possess unique clinical and biological features, and they are present in over 70% cases of infant leukemia (see, e.g., Biondi A, Cimino G, Pieters R, Pui C H (2000) Blood 96: 24-33) and in general account for approximately 5% of ALLs, 5%-10% of AMILs, and almost all cases of mixed-lineage leukemia (see, e.g., Huret J L, Dessen P, Bernheim A (2001) Leukemia 15: 987-989). Patients with leukemia harboring MLL translocations have a highly unfavorable prognosis with current treatments (see, e.g., Slany R K (2005) Hematol Oncol 23: 1-9). Thus novel therapeutic strategies are needed.